Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The neurofibromatosis 2 (NF2) gene-encoded protein, named merlin, may function as a molecular linkage connecting cytoskeleton and plasma membrane. Merlin is thought to play a crucial role as a tumor suppressor not only in hereditary NF2-related tumors, but also in sporadic tumors such as schwannomas, meningiomas and gliomas. Using a merlin-expression vector system, we raised specific antiserum against merlin. We observed the intracellular distribution of merlin in cultured glioma cells, and further investigated merlin expression in 116 human brain tumors. Immunofluorescence microscopy revealed that merlin was localized beneath the cell membrane and concentrated at cell-to-cell adhesion sites, where actin filaments are densely associated with plasma membrane. By immunohistochemistry, none of the schwannomas from either NF2 patients or sporadic cases showed any immunoreactivity, while normal Schwann cells of cranial nerves were immunopositive. In meningiomas, merlin expression was frequently seen in the meningothelial subtype (8/10, 80%), but no expression could be detected in either the fibrous or the transitional variant. Most normal astrocytes were negative; however, reactive astrocytes often expressed merlin. Glioblastomas and anaplastic astrocytomas were found to be strongly positive, and focal positive staining was observed in fibrillary and pilocytic astrocytomas. Thus, the loss of merlin appears to be integral to schwannoma formation and the differential pathogenesis of meningioma subtypes. However, merlin alterations do not appear to play a critical role in either the tumorigenesis or malignant transformation of neoplastic astrocytes.
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PMID:Expression of neurofibromatosis 2 protein in human brain tumors: an immunohistochemical study. 908 53

Neurofibromatosis 2 (NF2) protein (merlin; schwannomin) is a tumor suppressor involved in tumorigenesis of NF2-associated and sporadic schwannomas and meningiomas. The protein shares the domain structure of three homologous proteins: ezrin, radixin and moesin (ERM). ERM proteins function as membrane organizers and may act as linkers between plasma membrane molecules, such as CD44 and ICAM-2, and the cytoskeleton. We analyzed the distribution and effects of transfected NF2 protein in COS-1, CHO and 293 cells, and endogenous NF2 protein in U251 glioma cells. The distribution was compared to ezrin, CD44 and F-actin. Both transfected and endogenous NF2 protein localized underneath the plasma membrane in a pattern typical of an ERM protein. In COS-1 transfectants, NF2 protein typically codistributed with ezrin but, in cells with poorly developed actin cytoskeleton, it replaced ezrin in filopodia and ruffling edges. NF2 protein colocalized with CD44, which in transfected cells accumulated into restructured cell membrane protrusions. The association of CD44 and NF2 protein was further suggested by binding of CD44 from cellular lysates to recombinant NF2 protein. Interaction between NF2 protein and the actin-containing cytoskeleton was indicated by partial colocalization, by cytochalasin B-induced coclustering, and by retention of NF2 protein in the detergent-insoluble fraction. Transfected NF2 protein induced morphogenic changes. The cells contained restructured membrane extensions and blebs, and CHO cells expressing NF2 protein were more elongated than control transfectants. In conclusion, NF2 protein possesses functional properties of an ERM family member.
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PMID:Neurofibromatosis 2 tumor suppressor protein colocalizes with ezrin and CD44 and associates with actin-containing cytoskeleton. 937 74

Ezrin, radixin and moesin (ERM) are homologous proteins, which are linkers between plasma membrane components and the actin-containing cytoskeleton. The ERM protein family members associate with each other in a homotypic and heterotypic manner. The neurofibromatosis 2 (NF2) tumor suppressor protein merlin (schwannomin) is structurally related to ERM members. Merlin is involved in tumorigenesis of NF2-associated and sporadic schwannomas and meningiomas, but the tumor suppressor mechanism is poorly understood. We have studied the ability of merlin to self-associate and bind ezrin. Ezrin was coimmunoprecipitated with merlin from lysates of human U251 glioma cells and from COS-1 cells transfected with cDNA encoding for merlin isoform I. The interaction was further studied and the association domains were mapped with the yeast two-hybrid system and with blot overlay and affinity precipitation experiments. The heterotypic binding of merlin and ezrin and the homotypic association of merlin involves interaction between the amino- and carboxy-termini. The amino-terminal association domain of merlin involves residues 1-339 and has similar features with the amino-terminal association domain of ezrin. The carboxy-terminal association domain cannot be mapped as precisely as in ezrin, but it requires residues 585-595 and a more amino-terminal segment. Unlike ezrin, merlin does not require activation for self-association but native merlin molecules can interact with each other. Heterodimerization between merlin and ezrin, however, occurs only following conformational alterations in both proteins. These results biochemically connect merlin to the cortical cytoskeleton and indicate differential regulation of merlin from ERM proteins.
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PMID:Homotypic and heterotypic interaction of the neurofibromatosis 2 tumor suppressor protein merlin and the ERM protein ezrin. 1003 39

Chordoid glioma of the third ventricle was recently reported as a novel tumor entity of the central nervous system with characteristic clinical and histopathological features (Brat et al., J Neuropathol Exp Neurol 57: 283-290, 1998). Here, we report on a histopathological, immunohistochemical and molecular genetic analysis of five cases of this rare neoplasm. All tumors were immunohistochemically investigated for the expression of various differentiation antigens, the proliferation marker Ki-67, and a panel of selected proto-oncogene and tumor suppressor gene products. These studies revealed a strong expression of GFAP, vimentin, and CD34. In addition, most tumors contained small fractions of neoplastic cells immunoreactive for epithelial membrane antigen, S-100 protein, or cytokeratins. The percentage of Ki-67 positive cells was generally low (<5%). All tumors showed immunoreactivity for the epidermal growth factor receptor and schwannomin/merlin. There was no nuclear accumulation of the p53, p21 (Waf-1) and Mdm2 proteins. To examine genomic alterations associated with the development of chordoid gliomas, we screened 4 tumors by comparative genomic hybridization (CGH) analysis. No chromosomal imbalances were detected. More focussed molecular genetic analyses revealed neither aberrations of the TP53 and CDKN2A tumor suppressor genes nor amplification of the EGFR, CDK4, and MDM2 proto-oncogenes. Our data strongly support the hypothesis that chordoid glioma of the third ventricle constitutes a novel tumor entity characterized by distinct morphological and immunohistochemical features, as well as a lack of chromosomal and genetic alterations commonly found in other types of gliomas or in meningiomas.
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PMID:Chordoid glioma of the third ventricle: immunohistochemical and molecular genetic characterization of a novel tumor entity. 1051

The neurofibromatosis 2 tumour suppressor merlin/schwannomin is structurally related to the ezrin-radixin-moesin family of proteins, which anchor actin cytoskeleton to specific membrane proteins and participate in cell signalling. Merlin inhibits cell growth with a yet unknown mechanism. As most tumour suppressors are linked to cell cycle control, we investigated merlin's behaviour during cell cycle. In glioma and osteosarcoma cells, endogenous merlin was targeted to the nucleus in a cell cycle-specific manner. Merlin accumulated perinuclearly at the G2/M phase, and shifted to the nucleus at early G1. During mitosis, merlin localized to mitotic spindles and at the contractile ring. Nuclear merlin was strongly reduced in confluent cells. Blocking of the CRM1/exportin nuclear export pathway led to accumulation of merlin in the nucleus. Activation of the p21-activated kinase or protein kinase A, which result in phosphorylation of merlin, did not affect its nuclear localization. Merlin regulates the activity of extracellular signal-regulated kinase 2 (ERK2) and nuclear localization of both proteins was induced by cell adhesion. Unlike ERK2, nuclear localization of merlin was not, however, dependent on intact actin cytoskeleton. These results link merlin to events related to cell cycle control and may help to resolve its tumour suppressor function.
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PMID:Cell cycle-dependent nucleocytoplasmic shuttling of the neurofibromatosis 2 tumour suppressor merlin. 1558 Feb 88

Mutations of the neurofibromatosis 2 (NF2) tumor suppressor gene have frequently been detected not only in schwannomas and other central nervous system tumors of NF2 patients but also in their sporadic counterparts and malignant tumors unrelated to the NF2 syndrome such as malignant mesothelioma, indicating a broader role for the NF2 gene in human tumorigenesis. However, the mechanisms by which the NF2 product, merlin or schwannomin, is regulated and controls cell proliferation remain elusive. Here, we identify a novel GTP-binding protein, dubbed NGB (referring to NF2-associated GTP binding protein), which binds to merlin. NGB is highly conserved between Saccharomyces cerevisiae, Caenorhabditis elegans, and human cells, and its GTP-binding region is very similar to those found in R-ras and Rap2. However, ectopic expression of NGB inhibits cell growth, cell aggregation, and tumorigenicity in tumorigenic schwanomma cells. Down-regulation and infrequent mutation of NGB were detected in human glioma cell lines and primary tumors. The interaction of NGB with merlin impairs the turnover of merlin, yet merlin does not affect the GTPase nor GTP-binding activity of NGB. Finally, the tumor suppressor functions of NGB require merlin and are linked to its ability to suppress cyclin D1 expression. Collectively, these findings indicate that NGB is a tumor suppressor that regulates and requires merlin to suppress cell proliferation.
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PMID:Identification and characterization of putative tumor suppressor NGB, a GTP-binding protein that interacts with the neurofibromatosis 2 protein. 1721 Jun 37

The lack of neurofibromatosis 2 tumor suppressor protein merlin leads to the formation of nervous system tumors, specifically schwannomas and meningiomas. Merlin is considered to act as a tumor suppressor at the cell membrane, where it links transmembrane receptors to the actin cytoskeleton. Several tumor suppressors interact with another component of the cytoskeleton, the microtubules, in a regulated manner and control their dynamics. In this work, we identify merlin as a novel microtubule-organizing protein. We identify two tubulin-binding sites in merlin, one residing at the N-terminal FERM-domain and another at the C-terminal domain. Merlin's intramolecular association and phosphorylation of serine 518 regulate the interaction between merlin and tubulin. Analysis of cultured glioma cells indicates colocalization between merlin and microtubules especially during cell division. In primary mouse Schwann cells only minor colocalization at the cell periphery of interphase cells is seen. However, these cells drastically change their microtubule organization upon loss of merlin indicating a functional association of the proteins. Both in vitro assays and in vivo studies in Schwann cells indicate that merlin promotes tubulin polymerization. The results show that merlin plays a key role in the regulation of the Schwann cell microtubule cytoskeleton and suggest a mechanism by which loss of merlin leads to cytoskeletal defects observed in human schwannomas.
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PMID:The tumor suppressor merlin interacts with microtubules and modulates Schwann cell microtubule cytoskeleton. 1756 81

Neurofibromatosis 2 (NF2) is an inherited cancer syndrome in which affected individuals develop nervous system tumors, including schwannomas, meningiomas, and ependymomas. The NF2 protein merlin (or schwannomin) is a member of the Band 4.1 superfamily of proteins, which serve as linkers between transmembrane proteins and the actin cytoskeleton. In addition to mutational inactivation of the NF2 gene in NF2-associated tumors, mutations and loss of merlin expression have also been reported in other types of cancers. In the present study, we show that merlin expression is dramatically reduced in human malignant gliomas and that reexpression of functional merlin dramatically inhibits both subcutaneous and intracranial growth of human glioma cells in mice. We further show that merlin reexpression inhibits glioma cell proliferation and promotes apoptosis in vivo. Using microarray analysis, we identify altered expression of specific molecules that play key roles in cell proliferation, survival, and motility. These merlin-induced changes of gene expression were confirmed by real-time quantitative PCR, Western blotting, and functional assays. These results indicate that reexpression of merlin correlates with activation of mammalian sterile 20-like 1/2-large tumor suppressor 2 signaling pathway and inhibition of canonical and noncanonical Wnt signals. Collectively, our results show that merlin is a potent inhibitor of high-grade human glioma.
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PMID:Merlin is a potent inhibitor of glioma growth. 1863 26

The human glioma tumor suppressor candidate region 2 gene product, GLTSCR2, also called 'protein interacting with carboxyl terminus 1' (PICT-1), has been implicated in the regulation of two major tumor suppressor proteins, PTEN and p53, and reported to bind the membrane-cytoskeleton regulator of cell signaling, Merlin. PICT-1 is a nucleolar protein, conserved among eukaryotes, and its yeast homolog has been functionally associated with ribosomal RNA processing. By means of confocal microscopy of EGFP and myc-tagged PICT-1 fusion proteins, we delineate that the nucleolar localization of PICT-1 is mediated by two independent nucleolar localization sequences (NoLS). Unlike most NoLSs, these NoLSs are relatively long with flexible boundaries and contain arginine and leucine clusters. In addition, we show that PICT-1 exhibits a nucleolar distribution similar to proteins involved in ribosomal RNA processing, yet does not colocalize precisely with either UBF1 or Fibrillarin under normal or stressed conditions. Identification of the precise location of PICT-1 and the signals that mediate its nucleolar localization is an important step towards advancing our understanding of the demonstrated influence of this protein on cell fate and tumorigenesis.
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PMID:Nucleolar localization of GLTSCR2/PICT-1 is mediated by multiple unique nucleolar localization sequences. 2229 50

Neurofibromatosis (NF) is a family of genetic diseases which are caused by dysfunction of either NF1 gene or NF2 gene. One in 3,000 people suffer from this tumor-carrying NF. NF1 gene product is a RAS GTPase activating protein (GAP) of 2,818 amino acids, which normally attenuates the GTP-dependent signal transducing activity of the G protein RAS. Dysfunction of this GAP leads to the abnormal activation of RAS, and eventually an oncogenic kinase called PAK1 as well. NF2 gene product is ''Merlin'' which directly inactivates PAK1. Thus, dysfunction of Merlin causes the abnormal activation of PAK1. In other words, dysfunction of NF1 gene (causing type 1 NF) is basically the same as dysfunction of NF2 gene (causing type 2 NF). In fact the growth of both NF1 and NF2 tumors requires PAK1, and all PAK1 blockers, synthetic chemicals or natural products, suppress the growth of these NF tumor cells both in vitro (cell culture) and in vivo (mice). However, until recently, no FDA-approved effective NF therapeutics is available on the market. Here a series of anti-PAK1 products shall be introduced, which would be potentially useful for the life-long treatment of NF patients in the future. These include the most potent HDAC (histone deacetylase) inhibitor FK228 (IC<sub>50</sub>: around 1 nM), that eventually blocks PAK1, the direct PAK1 inhibitor PF3758309 (IC<sub>50</sub>: around 10 nM), a CAPE (caffeic acid phenethyl ester)-based propolis extract called ''Bio 30'' from NZ (New Zealand), and an ARC (artepillin C)-based green propolis extract (GPE) from Brazil. Although the first two drugs are potent, none of them is available on the market as yet. The last two natural (bee-made) products are available on the market, and have been used for the therapy of NF and tuberous sclerosis (TSC) as well as many PAK1-dependent solid cancers such as breast and pancreatic cancers as well as glioma, which altogether represent more than 70% of all human cancers. Since PAK1 is not essential for the normal cell growth, propolis extracts cause no side effects.
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PMID:Effective neurofibromatosis therapeutics blocking the oncogenic kinase PAK1. 2246 37


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